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    NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis.

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    Name:
    Sengupta et al Mol Cell Final.pdf
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    Description:
    Accepted manuscript
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    NSD2 figures_Final.pdf
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    Type
    Article
    Authors
    Sengupta, Deepanwita
    Zeng, Liyong
    Li, Yumei
    Hausmann, Simone
    Ghosh, Debopam
    Yuan, Gang
    Nguyen, Thuyen N
    Lyu, Ruitu
    Caporicci, Marcello
    Morales Benitez, Ana
    Coles, Garry L
    Kharchenko, Vladlena
    Czaban, Iwona
    Azhibek, Dulat
    Fischle, Wolfgang cc
    Jaremko, Mariusz cc
    Wistuba, Ignacio I
    Sage, Julien
    Jaremko, Lukasz cc
    Li, Wei
    Mazur, Pawel K
    Gozani, Or
    KAUST Department
    Bioscience
    Biological and Environmental Science and Engineering (BESE) Division
    Bioscience Program
    Date
    2021-11-04
    Online Publication Date
    2021-11-04
    Print Publication Date
    2021-11
    Embargo End Date
    2022-09-23
    Submitted Date
    2021-05-11
    Permanent link to this record
    http://hdl.handle.net/10754/671927
    
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    Show full item record
    Abstract
    The etiological role of NSD2 enzymatic activity in solid tumors is unclear. Here we show that NSD2, via H3K36me2 catalysis, cooperates with oncogenic KRAS signaling to drive lung adenocarcinoma (LUAD) pathogenesis. In vivo expression of NSD2$_{E1099K}$, a hyperactive variant detected in individuals with LUAD, rapidly accelerates malignant tumor progression while decreasing survival in KRAS-driven LUAD mouse models. Pathologic H3K36me2 generation by NSD2 amplifies transcriptional output of KRAS and several complementary oncogenic gene expression programs. We establish a versatile in vivo CRISPRi-based system to test gene functions in LUAD and find that NSD2 loss strongly attenuates tumor progression. NSD2 knockdown also blocks neoplastic growth of PDXs (patient-dervived xenografts) from primary LUAD. Finally, a treatment regimen combining NSD2 depletion with MEK1/2 inhibition causes nearly complete regression of LUAD tumors. Our work identifies NSD2 as a bona fide LUAD therapeutic target and suggests a pivotal epigenetic role of the NSD2-H3K36me2 axis in sustaining oncogenic signaling.
    Citation
    Sengupta, D., Zeng, L., Li, Y., Hausmann, S., Ghosh, D., Yuan, G., … Gozani, O. (2021). NSD2 dimethylation at H3K36 promotes lung adenocarcinoma pathogenesis. Molecular Cell, 81(21), 4481–4492.e9. doi:10.1016/j.molcel.2021.08.034
    Sponsors
    We thank members of the Gozani and Mazur labs for critical reading of the manuscript. This work was supported in part by grants from the NIH (R35 GM139569 to O.G., R01 CA236118 to O.G. and P.K.M., K99 CA255936 to S.M., and R01HG007538, R01CA193466, and R01CA228140 to W.L.); intramural funds from KAUST (to W.F., L.J., and M.J.); and AACR, NETRF, a DOD PRCRP career development award (CA181486), a career enhancement grant from The University of Texas NIH SPORE in Lung Cancer (P50CA070907), and the Andrew Sabin Family Foundation Scientist and CPRIT Scholar in Cancer Research (RR160078) (to P.K.M.). D.S. was supported by a grant from the Stanford Maternal and Child Health Research Institute. This work was also supported in part by the Stanford Cancer Institute, a NCI-designated Comprehensive Cancer Center.
    Journal
    Molecular cell
    DOI
    10.1016/j.molcel.2021.08.034
    PubMed ID
    34555356
    ae974a485f413a2113503eed53cd6c53
    10.1016/j.molcel.2021.08.034
    Scopus Count
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    Articles; Biological and Environmental Science and Engineering (BESE) Division; Bioscience Program

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